Clofazimine Inhalation for Nontuberculous Mycobacterial Infections

(ICoN-1 Trial)

Recruiting at 51 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Mannkind Corporation

Must be taking: Guideline-based therapy

Must not be taking: Amikacin, Bedaquiline, Prednisone

Disqualifiers: Cystic fibrosis, Active tuberculosis, others

Pivotal Trial (Near Approval)

Prior Safety Data

Approved in 4 Jurisdictions

Trial Summary

What is the purpose of this trial?

This clinical trial is designed to compare the efficacy and safety of Clofazimine Inhalation Suspension versus placebo when added to guideline-based therapy (GBT)

Will I have to stop taking my current medications?

The trial requires participants to have been on a stable multi-drug regimen for their lung infection for at least 6 months before joining, with no changes in the last 2 months. This suggests you should continue your current medications as long as they meet these criteria.

What data supports the effectiveness of the drug Clofazimine Inhalation Suspension for treating nontuberculous mycobacterial infections?

Research shows that clofazimine has strong activity against nontuberculous mycobacteria in lab studies, and an inhaled form of the drug demonstrated promising results in animal studies by maintaining high levels in lung tissue, which could help treat lung infections effectively while reducing side effects. ^{1 2 3 4 5}

Is clofazimine inhalation safe for humans?

Clofazimine inhalation has been studied in animals and shows promise in reducing toxicity compared to oral forms, as it delivers the drug directly to the lungs, minimizing systemic exposure. While these studies suggest it may be safer, more research in humans is needed to confirm its safety. ^{1 2 6 7 8}

What makes Clofazimine Inhalation Suspension unique for treating nontuberculous mycobacterial infections?

Clofazimine Inhalation Suspension is unique because it is administered through inhalation, which directly targets the lungs where nontuberculous mycobacterial infections often occur, potentially increasing its effectiveness compared to traditional oral or intravenous routes. ^{2 3 4 9 10}

Research Team

Wassim Fares, MD

Principal Investigator

Mannkind Corporation

Eligibility Criteria

Adults aged 18-85 with lung disease caused by Mycobacterium Avium Complex (MAC), who are already on a multi-drug regimen for at least 6 months, can produce sputum samples, and have no recent use of certain drugs or conditions like active cancer. Women must not be pregnant and agree to contraception; men must also agree to contraception if they can father children.

Inclusion Criteria

FEV1 ≥40% of predicted during screening

I can produce the required amount of sputum for the test.

I have been on a specific treatment for NTM lung infection for at least 6 months without changes.

Exclusion Criteria

Inability to inhale with a nebulizer, in the opinion of the investigator

Known hypersensitivity to any of the ingredients or excipients of clofazimine

I haven't had cancer treatments in the last 3 years and don't expect any during the study.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment (Part A)

Participants receive Clofazimine Inhalation Suspension or placebo daily for 28 days in Cycle 1, followed by 56 days off treatment, and then resume daily for 28 days in Cycle 2

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension (Part B)

Qualified participants receive Clofazimine Inhalation Suspension from Study Month 7 through Study Month 22

16 months

Treatment Details

Interventions

• Clofazimine Inhalation Suspension (Anti-infective agent)

Trial Overview The trial is testing the effectiveness and safety of Clofazimine Inhalation Suspension compared to a placebo in patients with MAC lung disease. Participants will continue their current drug regimens alongside the trial medication or placebo.

Participant Groups

Group I: Clofazimine Inhalation Suspension Experimental Treatment 1 Intervention

MNKD-101 (Clofazimine Inhalation Suspension) is a micronized suspension with a concentration of 20 mg/mL. Study drug will be inhaled using the PARI breath-enhanced jet nebulizer system daily for 28 days in Cycle 1. Cycle 2 will commence after 56 days off treatment and resume daily for 28 days. Dose: 80 mg

Group II: Placebo Placebo Group 1 Intervention

The placebo is comprised of isotonic saline (0.9% weight/volume sodium chloride). Study drug will be inhaled using the PARI breath-enhanced jet nebulizer system daily for 28 days in Cycle 1. Cycle 2 will commence after 56 days off treatment and resume daily for 28 days.

Clofazimine Inhalation Suspension is already approved in Japan for the following indications:

Approved in Japan as MNKD-101 for:

• Nontuberculous mycobacterial (NTM) lung disease

Who Is Running the Clinical Trial?

Mannkind Corporation

Lead Sponsor

Trials

61

Recruited

8,400+

Michael E. Castagna

Mannkind Corporation

Chief Executive Officer since 2017

PharmD from Massachusetts College of Pharmacy & Sciences, MBA from The Wharton School of Business at the University of Pennsylvania

Burkhard Blank

Mannkind Corporation

Chief Medical Officer since 2021

MD

Findings from Research

A novel inhaled formulation of clofazimine was tested in canines over 28 days, showing significant drug retention in lung tissue and maintaining concentrations well above the minimum inhibitory concentration (MIC) for nontuberculous mycobacteria (NTM).

This inhalation method may reduce systemic toxicity associated with traditional oral or parenteral clofazimine treatments, providing a more effective and safer option for managing NTM infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clofazimine Inhalation Suspension Demonstrates Promising Toxicokinetics in Canines for Treating Pulmonary Nontuberculous Mycobacteria Infection. Kunkel, M., Doyle-Eisele, M., Kuehl, P., et al.[2023]

Clofazimine demonstrated strong in vitro activity against 80 isolates of rapidly growing nonchromogenic mycobacteria, inhibiting 96% of the strains at concentrations of 1 microgram/ml or less.

The drug shows potential efficacy specifically against Mycobacterium fortuitum and M. chelonae, suggesting it could be a valuable treatment option for infections caused by these bacteria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro activity of clofazimine against rapidly growing nonchromogenic mycobacteria. Ausina, V., Condom, MJ., Mirelis, B., et al.[2021]

Clofazimine has shown effectiveness against various nontuberculous mycobacteria, making it a potential treatment option for infections like Mycobacterium avium.

In a unique case, a woman with cystic fibrosis and a macrolide-resistant Mycobacterium avium infection was successfully treated with clofazimine administered through a gastrostomy tube, highlighting a novel method of delivery for this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel Administration of Clofazimine for the Treatment of Mycobacterium avium Infection. Valinetz, E., Stankiewicz Karita, H., Pottinger, PS., et al.[2022]

Clofazimine shows varying minimal inhibitory concentrations (MICs) against different strains of nontuberculous mycobacteria, with lower MICs (≤ 0.25 mg/L) being associated with a higher likelihood of achieving negative sputum culture conversion in patients.

In a study of 20 patients treated with clofazimine, 40% achieved negative culture conversion, particularly those with MIC values ≤ 0.25 mg/L, suggesting that clofazimine could be an effective treatment option for NTM-PD in cases with lower MICs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Minimal Inhibitory Concentration of Clofazimine Among Clinical Isolates of Nontuberculous Mycobacteria and Its Impact on Treatment Outcome. Kwak, N., Whang, J., Yang, JS., et al.[2021]

Clofazimine (CFZ) combined with clarithromycin (CLR) and ethambutol (EMB) significantly reduced lung bacterial counts in a mouse model of Mycobacterium avium, showing improved efficacy compared to untreated controls.

While CFZ added to CLR enhanced treatment effectiveness, it was less effective than the standard CLR-RIF-EMB combination, indicating that while CFZ shows promise, further studies are needed to optimize its use in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic Activity of Clofazimine and Clarithromycin in an Aerosol Mouse Model of Mycobacterium avium Infection. Lanoix, JP., Joseph, C., Peltier, F., et al.[2021]

Inhaled delivery of micronized clofazimine (CFZ) significantly increases drug concentrations in the lungs and provides faster bactericidal effects against tuberculosis compared to oral administration, as shown in a study with BALB/c mice.

The formulation of CFZ is stable and resistant to degradation, making it a suitable option for treating TB in low-resource settings where cold-chain storage is challenging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Respirable Clofazimine Particles Produced by Air Jet Milling Technique Are Efficacious in Treatment of BALB/c Mice with Chronic Mycobacterium tuberculosis Infection. Brunaugh, AD., Walz, A., Warnken, Z., et al.[2023]

In a study testing 14 compounds for their effectiveness against Mycobacterium intracellulare, only clofazimine and chaulmoogric acid demonstrated significant activity.

Clofazimine, known for its minimal side effects, shows promise as a potential treatment for M. intracellulare infections, warranting further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antimycobacterial activity of some potential chemotherapeutic compounds. Damle, P., McClatchy, JK., Gangadharam, PR., et al.[2019]

Clofazimine has been identified as an ideal positive control for preclinical studies on Mycobacteroides abscessus (Mab) pulmonary disease, as it is well-tolerated, requires only once-daily dosing, and effectively reduces Mab burden in mouse models.

In a six-week study with C3HeB/FeJ and BALB/c mice, clofazimine at a dosage of 25 mg/kg once daily significantly decreased Mab levels in the lungs, supporting its use in future efficacy assessments of new treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clofazimine as a comparator for preclinical efficacy evaluations of experimental therapeutics against pulmonary M. abscessus infection in mice. Sriram, D., Wahi, R., Maggioncalda, EC., et al.[2023]

Clofazimine was found to be a safe and reasonably tolerated treatment option for patients with nontuberculous mycobacterial (NTM) infections, with 50% of patients showing negative NTM cultures within 12 months of treatment.

In a study of 112 patients, including both pediatric and adult individuals with cystic fibrosis and non-cystic fibrosis, clofazimine demonstrated clinical efficacy, particularly in those with refractory disease, suggesting it could be a valuable alternative in NTM treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Effectiveness of Clofazimine for Primary and Refractory Nontuberculous Mycobacterial Infection. Martiniano, SL., Wagner, BD., Levin, A., et al.[2018]

In a study of 44 patients with nontuberculous mycobacterial (NTM) infections treated with clofazimine, 58% achieved treatment success, indicating that clofazimine can be an effective addition to multi-class antibiotic regimens for these difficult-to-treat infections.

Clofazimine was well-tolerated among patients, and those infected with the Mycobacterium abscessus group had a higher likelihood of treatment success, while macrolide resistance was associated with poorer outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clofazimine for treatment of multidrug-resistant non-tuberculous mycobacteria. Pfaeffle, HOI., Alameer, RM., Marshall, MH., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Clofazimine Inhalation Suspension Demonstrates Promising Toxicokinetics in Canines for Treating Pulmonary Nontuberculous Mycobacteria Infection. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

In vitro activity of clofazimine against rapidly growing nonchromogenic mycobacteria. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Novel Administration of Clofazimine for the Treatment of Mycobacterium avium Infection. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Minimal Inhibitory Concentration of Clofazimine Among Clinical Isolates of Nontuberculous Mycobacteria and Its Impact on Treatment Outcome. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Synergistic Activity of Clofazimine and Clarithromycin in an Aerosol Mouse Model of Mycobacterium avium Infection. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Respirable Clofazimine Particles Produced by Air Jet Milling Technique Are Efficacious in Treatment of BALB/c Mice with Chronic Mycobacterium tuberculosis Infection. [2023]

7. Scotland pubmed.ncbi.nlm.nih.gov

Antimycobacterial activity of some potential chemotherapeutic compounds. [2019]

8. Scotland pubmed.ncbi.nlm.nih.gov

Clofazimine as a comparator for preclinical efficacy evaluations of experimental therapeutics against pulmonary M. abscessus infection in mice. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Safety and Effectiveness of Clofazimine for Primary and Refractory Nontuberculous Mycobacterial Infection. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Clofazimine for treatment of multidrug-resistant non-tuberculous mycobacteria. [2021]